Increased age-related variability of motor function indicates that some older adults are more vulnerable to motor decline than others. Impaired motor function in vulnerable adults, leads to loss of ability to work and to lost independence, ultimately leading to substantially greater costs to an aging society. This proposal adopts a new and innovative approach to understanding motor function and motor fatigue (exercise induced reduction in strength) in vulnerable older men and women. We explore the large inter-subject variability that occurs with increased age to provide insight to a genetic mechanism underlying motor decline of the lower limb in men and women. Specifically, we associate inter-subject variability of motor function and fatigue with inheritance of the 4 allele of the apolipoprotein-E (APOE) gene. We propose that APOE 4 carriers have reduced effectiveness of the glutamate receptor (NMDA) in motor cortical areas and a subsequent reduction in intracortical excitability and lower neural drive during motor tasks than APOE 4 non carriers: these mechanisms will be assessed with transcranial magnetic stimulation (TMS). Despite the substantive potential for intervention with vulnerable older adults, the cortical mechanisms underlying motor decline have received very limited attention. APOE 4 inheritance is typically associated with risk of Alzheimer's Disease but was recently shown to increase the risk of motor function decline with advanced age. Whether motor fatigue during dynamic tasks, which is a common component of ergonomic and daily activities, exacerbates impaired strength and power in older adults with APOE 4 inheritance is unknown. Thus, we hypothesize that impaired motor function and greater fatigue among older adults is related to possession of the APOE 4 allele and mediated by reduced effectiveness of the glutamate receptor in motor cortical areas, reduced intracortical facilitation and decreased neural drive from motor cortical centers. Aim 1 will determine whether APOE 4 allele possession is associated with increased motor fatigue in lower limb muscles and decreased functionality of motor tasks (walking speed, balance, stair climbing) among independently living older men and women. Aim 2 will compare intracortical facilitation and neural drive from the motor cortex during motor function tasks before and after motor fatigue among older men and women who are carriers and non-carriers of APOE 4. Intracortical facilitation and supraspinal drive will be quantified with TMS of the motor cortex. Because older women are weaker and closer to functional performance thresholds without added vulnerability, sex differences will be explored to determine if older men or women are more vulnerable to motor impairment with APOE 4 inheritance associated with reduced intracortical facilitation and supraspinal drive. The results will have high impact by: (1) providing insight into successful aging and the mediating role of intracortical facilitation and supraspinal drive; (2) identifying 'healthy' but vulnerable older adults for accelerated motor decline, and (3) providing a rationale for early, targeted strategies to offset altered neural networks and early motor decline.